Strategies in the synthesis of dibenzo[b,f]heteropines

The dibenzo[b,f]azepine skeleton is important in the pharmaceutical industry, not only in terms of existing commercial antidepressants, anxiolytics and anticonvulsants, but also in reengineering for other applications. More recently, the potential of the dibenzo[b,f]azepine moiety in organic light emitting diodes and dye-sensitized solar cell dyes has been recognised, while catalysts and molecular organic frameworks with dibenzo[b,f]azepine derived ligands have also been reported. This review provides a brief overview of the different synthetic strategies to dibenzo[b,f]azepines and other dibenzo[b,f]heteropines.

in 1974, is recommended. While the review is lacking modern metal catalysis, it is still an excellent work covering early syntheses and properties. An analogous review published by Olivera et al. [29] covers the topic of dibenzo[b,f]oxepines (1b) up to 2002.
Other heteroatoms (e.g., O, N, S, P, B and Si) in the heterocyclic ring result in analogues of dibenzo[b,f]azepines and -oxepines. This group of compounds will thus be broadly referred to as dibenzo[b,f]heteropines (1).
The first section of this review will cover the synthesis of dibenzo[b,f]heteropines (1) and 10,11-dihydrodibenzo[b,f]heteropines (2). The following section will briefly touch on functionalisation of the scaffold.
While some reports are limited to the introduction of a single heteroatom, e.g., nitrogen in the case of azepines 1a or oxygen in the case of oxepines 1b, some approaches allow for the incorporation of a diverse scope of heteroatoms (e.g., O, N, S, P, B and Si) and may give access to a range of dibenzo[b,f]heteropines 1 using common intermediates [30,31]. Therefore, this section will be broadly organised by reaction type responsible for ring closure.
While extensive patent literature documenting methods exists, it is difficult to find accurate, up to date information regarding the industrial synthesis of 5H-dibenzo[b,f]azepine (1a) and derivatives. The following strategy (Scheme 1) was noted by chemists at Novartis as standard in 2005 [32].

Catalytic dehydrogenation
An early synthesis of 5H-dibenzo[b,f]azepine (1a) involved the gas phase dehydrogenation of 10,11-dihydro-5Hdibenzo[b,f]azepine (2a) to 1a in poor yield (20-50%) [39]. The starting material 2a was distilled through a heated (≈150 °C) column packed with Pd/C and glass wool. Crude 1a was collected as a solid and purified. Further research has been conducted on the effect of catalyst choice and composition for large scale synthesis. Knell et al. [40,41] reported a comparison of several catalysts, which included potassium-promoted iron, cobalt and manganese oxide catalysts, for the synthesis of 1a. Industrially, 1a is produced by the vapour phase dehydration of 2a over an iron/potassium/chromium catalyst system (Scheme 4) [42].

Ring expansion through rearrangement
Several methods utilise ring expansion to prepare the required 7-membered azepine and oxepine rings of 1a and 1b.
Independently, in an effort to synthesise phenothiazine isosteres, Craig et al. [39] prepared 1a via a Wagner-Meerwein  rearrangement of 23 with P 2 O 5 (Scheme 5) the following year. The method was used to successfully synthesise unsubstituted as well as chloro-substituted derivatives of 1a. Storz et al. [44] have reported on an analogous method to prepare dibenzo[b,f]oxepines 1b through the rearrangement of 9-(αhydroxyalkyl)xanthenes.

Ring expansion of 2-(9-xanthenyl)malonates
Oxidative ring expansion of 2-(9-xanthenyl)malonates 24 was reported by Cong et al. [45] as a method for the synthesis of Stopka et al. [46] reported on tandem C-H functionalisation and ring expansion as an alternative to the Wagner-Meerwin rearrangement (Scheme 7). Several azepine 30 and oxepine 31 examples were prepared in good yield from the respective acridane (26) and xanthene (27) derivatives. As an alternative to the thermal Wagner-Meerwin rearrangement (Scheme 5 and Scheme 6), which requires elevated temperatures, Stopka et al. [46] used mild copper-catalysed oxidative conditions to effect the transformation to 30 and 31.

Ring expansion of N-arylindoles (41)
The polyphosphoric acid (PPA)-catalysed rearrangement of N-arylindoles 41 was first reported by Tokmakov and Grandberg [48]. The reaction provided moderate yields with a simple 2 step linear sequence from indole 39. The reaction requires heating at elevated temperatures and reaction times of up to 150 hours. The electronic properties of the rings have a signifi- Elliott et al. [47] investigated several methods to synthesise substituted dibenzo[b,f]azepines, which included the ring expansion of N-arylindoles 41 to synthesise 43 and the rearrangements of 9-acridine methanol 37 (Scheme 8) and N-arylindoles 41 (Scheme 9). The authors reported an excellent two-step synthesis of substituted dibenzo[b,f]azepines 43 via commercially available substituted indole 39 precursors based on the method of Tokmakov and Grandberg [48]. N-Arylindoles 41 were successfully synthesised via a copper-catalysed Ullmantype coupling or a palladium-catalysed Buchwald-Hartwig amination (Scheme 9). Performing the rearrangement at high temperatures resulted in the undesirable formation of acridine byproducts 44. Cleaner reaction profiles could be obtained at a lower temperature (100 °C). In contrast to the effect reported for NO 2 and CF 3 substituents by Tokmakov and Grandberg [48], electron-withdrawing halogen substituents on the aryl ring did not prevent rearrangement to dibenzo[b,f]azepine 43 [49]. The isolated yield of unsubstituted 43 was good (67%), however, substitution resulted in a decreased yield. While fluoro groups were well tolerated, a major drawback of the method is the acid-catalysed dehalogenation of chloro-and bromo-substituted dibenzo[b,f]azepines. The brominated analogue was only isolated in 5% yield, compared to 67% for the unsubstituted 43.
In addition, several methods of carboxamidation were tested, thus allowing the authors to synthesize carbamazepine (CBZ) derivatives of 43.

Metal-catalysed cyclisation
Diverse metal-catalysed coupling methods exist for the preparation of the dibenzo[b,f]heteropine ring system. The following approaches are broadly categorised according to the major or final catalytic step employed to form the 7-membered heterocycle as several synthetic methods use multiple catalytic steps.

Buchwald-Hartwig amination, etherification and thioetherification
The Buchwald-Hartwig reaction gives access to arylamines, -ethers and thioethers from aryl halides and triflates through palladium catalysis [50,51]. Scheme 10 provides a retrosynthesis of amination in the synthesis of dibenzo[b,f]azepine 45 as an example. Arnold et al. [30] reported an excellent method for the convergent synthesis of variable sized dibenzo-fused heterocycles. Among these, Heck reaction conditions allowed for the coupling of aryl acrylates 50 to aryl halides 48 and 49, fol-lowed by intramolecular Pd-catalysed amination or etherification to give C-10 carboxylates of dibenzo[b,f]azepine 55 and dibenz[b,f]oxepine 54 in good yield (Scheme 11). However, no ring-substituted derivatives were reported. The authors used alpha-substituted acrylates to reduce the effect of poor endo/exo regioselectivity in the intramolecular Heck reaction (cf. Scheme 19).
Božinović et al. [52] reported the synthesis of symmetrical 5H-dipyridoazepines 60a and unsymmetrical 5H-pyridobenzazepines 60b via cyclisation of 2,2'-dihalostilbene analogue 58 through a Pd-catalysed double Buchwald-Hartwig amination. The stilbene analogues 58 were prepared by a Wittig reaction with reported yields of the desired Z-isomer around 55%. The amination step was performed on a series of primary alkylamines (RNH 2 ) with moderate to good yields (47-87%). The strategy was also successfully applied to the synthesis of thiepines 59 with moderate yield (49-51%, Scheme 12). amines and the reaction time varied between 11 and 24 hours. Fluoro, chloro, nitrile, alkyl, and methyl ether aromatic substituents were tolerated.
Unsymmetrical 10,11-dihydro-5H-dibenzo[b,f]azepine derivatives 71 have been synthesised by ortho-bromination of functionalised dihydrostilbenes 67, followed by intramolecular cyclisation using Buchwald-Hartwig amination (Scheme 14) [54]. The pathway relies on a double Sonogashira coupling [(i) and (iii)], reduction (iv), and bromination (v), followed by Buchwald-Hartwig amination (viii) (Scheme 14). While interesting, the reaction has limited substrate scope due to the reliance on a late-stage bromination. To achieve the correct ortho-bromo substitution pattern, it requires a para-substituted ester as a directing group. The strategy furthermore cannot access 5H-dibenzo[b,f]azepines 1a as the ethylene bridge would cross react with the brominating agent [55,56].  final Mizoroki-Heck reaction will be discussed in the following section. with reports of poor selectivity when performing intramolecular Heck reactions (cf. Jepsen et al. [60]).

Mizoroki-Heck coupling
An analogous reaction pathway by Jepsen et al. [60] was used to synthesise dibenzo[b,f]thiapines 1c and dibenzo[b,f]oxepines 1b in three steps through a styrene (95 and 96) intermediate ( Scheme 19). While the reported conversion was excellent, the yield was low due to moderate selectivity, resulting in a mixture of 7-endo (1c and 1b) and 6-exo (97 and 98) cyclised products.

Catellani-type reaction
The Catellani reaction involves palladium-norbornene cooperative catalysis to functionalise the ortho-and ipso-positions of aryl halides by alkylation, arylation, amination, acylation, thiolation, etc. [63]. In the follow-up reported in 2018 [65], the method was extended to aryl bromides and electron-withdrawing groups. The authors found that the addition of potassium iodide, and thus in situ palladium-catalysed halogen exchange, improved the yield of dibenzo[b,f]azepine 110. Unsymmetrical derivatives of 110 containing -CO 2 Me, -CF 3 , -NO 2 and -CN substituents were synthesised in moderate to good yield (35-82%).

Ring-closing metathesis
Olefin metathesis is a metal-catalysed reaction wherein carbon-carbon double bonds are cleaved and formed through an intermediate cyclometallacarbene 114, thus allowing for transalkylidenation and the formation of mixed alkenes 115 (Scheme 24) [66]. Variations of this reaction include alkyne metathesis [67] and carbonyl metathesis [68].

Alkyne-aldehyde metathesis
Bera et al. [69] reported on the synthesis of a series of 10-acyldibenzo[b,f]oxepines 125 by alkyne-aldehyde metathesis catalysed by iron(III) chloride (Scheme 26). Alkyne-carbonyl metathesis is proposed to proceed via [2 + 2] cycloaddition and -reversion steps, catalysed by a Brønsted or Lewis acid, with the catalyst proposed to form a σ-complex with the carbonyl group and/or a π-complex with the alkyne [68].

Hydroarylation
The construction of an N-triarylated dibenzo[b,f]azepine scaffold 129 by means of Au(I)-catalysed hydroarylation was reported by Ito et al. [70]. While the attempted synthesis of an N-phenyldibenzazepine derivative 127 was unsuccessful, the authors were able to prepare a fused carbazoledibenzo[b,f]azepine 129 in 90% yield via a gold/silver catalyst system (Scheme 27).

Oxidative C-C coupling
Whereas oxidative C-C coupling precedes amination in the industrial route to 5H-dibenzo[b,f]azepine, oxidative C-C coupling may also be the final step in the construction of the dibenzo[b,f]heteropine skeleton.
Comber and Sargent [18] synthesised pacharin (13) using a novel method through oxidation of a bisphosphonium diphenyl ether prepared in situ from dibromide 130 (Scheme 28). On treatment with base and exposure to oxygen, the diylide intermediate underwent oxidative coupling to give the isopropylprotected dibenzo[b,f]oxepine in good yield (65%). Subsequent deprotection of the isopropyloxy group with BCl 3 gave 13 in good yield.

Functionalisation of dibenzo[b,f]azepine
Dibenzo[b,f]azepine (1a) can be used as a precursor to complex molecules based on the dibenzazepine scaffold. Several positions of 1a have been successfully functionalised as shown in Figure 6.

N-Functionalisation
The secondary amine 5H-dibenzo[b,f]azepine (1a) and derivatives follow standard reactions of secondary arylamines and as such will be only briefly discussed with selected examples.
Huang and Buchwald [73] reported a palladium-catalysed arylation of 1a. Treatment of 1a with aryl halide 140 or 141 gave excellent yields of N-aryldibenzo[b,f]azepines 142 (Scheme 31). The reaction conditions were screened with several biarylphosphine ligands and Pd sources. Excellent yields were achieved with a low catalyst loading of RuPhos (L6) fourth generation palladacycle precatalyst L6 Pd G4 (Scheme 31).  The authors evaluated an extensive series of aryl halides. The yield proved to be good to excellent and sterically hindered aryl rings were tolerated. This method was applied by Huang et al. [74] to prepare a series of fluorescent compounds in excellent yield.
Copper-and nickel-catalysed arylation were reported as alternatives to the Pd-catalysed arylation of 1a (Scheme 32). Yao et al. An industrial synthesis of opipramol (5) by alkylation of 1a was patented in 1997 [79]. The process involves the alkylation of iminostilbene (1a) as a critical intermediate step (Scheme 33C). The alkyl halide linker of 148 was further functionalised by reaction with piperazine derivative 149 to give opipramol (5).

Conclusion
The dibenzo[b,f]heteropine template is an important feature in several commercial and lead active pharmaceutical ingredients, biologically active natural products, dyes in OLEDs and dye sensitive solar cells, and in certain ligands. This review provides an overview of the different synthetic strategies towards dibenzo[b,f]azepines and other dibenzo[b,f]heteropines, and the functionalisation thereof. Modern metal-catalyzed methods to introduce the C-C bridge include the Heck reaction, the Sonogashira reaction, Suzuki coupling and ring-closing metathesis, whereas Buchwald-Hartwig type reactions and Ullman etherification entails the palladium or copper-catalysed formation of a carbon-heteroatom bond. Despite significant successes and facile access to the core tricyclic motif, access to dibenzo[b,f]heteropines with disparately substituted aromatic rings fused to the heterocyclic ring and varied substitution patterns is still limited. This void is particularly true for dibenzo[b,f]heteropines with multiple electron-donating substituents on both rings.

Funding
This work was supported by the National Research Foundation of South Africa (Grant numbers 118076 and 138297). The opinions, findings and conclusions or recommendations expressed in this publication are those of the authors alone and the NRF accepts no liability whatsoever in this regard.